Methods of treating dermatological disorders and inducing interferon biosynthesis with shorter durations of imiquimod therapy

ABSTRACT

Pharmaceutical formulations and methods for the topical and/or transdermal delivery of imiquimod, including creams, ointments and pressure-sensitive adhesive compositions to treat dermatological disorders, namelyl, viral infections, such as Type I or Type II Herpes simplex infections and genital and perianal warts, actinic deratosis and superficial basal cell carcinoma, and to induce interferon biosynthesis to achieve an antiviral effect, with shorter durations of therapy, than currently approved for imiquimod by the Food &amp; Drug Administration (“FDA”).

FIELD OF THE INVENTION

This invention pertains to methods and pharmaceutical formulations forthe topical or transdermal delivery of1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine, i.e., imiquimod. Moreparticularly, it pertains to creams, ointments, foams, gels, lotions,pressure sensitive adhesive coatings and adhesive-coated sheetmaterials, which contain low dose imiquimod, that enhance skinpenetration of drugs to treat dermatological disorders, namely, viralinfections, such as Type I or Type II Herpes simplex infections andexternal genital and perianal warts, actinic keratosis and superficialbasal cell carcinoma, and to induce interferon biosynthesis to achievean antiviral effect, with shorter durations of therapy, than currentlyapproved for imiquimod by the Food & Drug Administration (“FDA”).

BACKGROUND

The compound 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine, known asimiquimod and commercially marketed in the U.S. under the brand nameAldara®, is disclosed in U.S. Pat No. 4,689,338 and described therein asan antiviral agent and as an interferon inducer, which is incorporatedherein by reference in its entirety. A variety of formulations fortopical administration of imiquimod are also described therein. ThisU.S. Pat. No. 4,689,338 is incorporated herein by reference in itsentirety

U.S. Pat. No. 4,751,087 discloses the use of a combination of ethyloleate and glyceryl monolaurate as a skin penetration enhancer fornitroglycerine, with all three components being contained in theadhesive layer of a transdermal patch, wherein this U.S. patent isincorporated herein by reference in its entirety.

U.S. Pat. No. 4,411,893 discloses the use ofN,N-dimethyldodecylamine-Noxide as a skin penetration enhancer inaqueous systems, wherein this U.S. patent is incorporated herein byreference in its entirety.

U.S. Pat. No. 4,722,941 discloses readily absorbable pharmaceuticalcompositions that comprise a pharmacologically active agent distributedin a vehicle comprising an absorption-enhancing amount of at least onefatty acid containing 6 to 12 carbon atoms and optionally a fatty acidmonoglyceride. Such compositions are said to be particularly useful forincreasing the absorption of pharmacologically active bases, whereinthis U.S. patent is incorporated herein by reference in its entirety.

U.S. Pat. No. 4,746,515 discloses a method of using glyceryl monolaurateto enhance the transdermal flux of a transdermally deliverable drugthrough intact skin, wherein this U.S. patent is incorporated herein byreference in its entirety.

U.S. Pat. No. 5,238,944 discloses topical formulations and transdermaldelivery systems containing1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, wherein this U.S. patentis incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

The present invention provides a substantially non-irritatingpharmaceutical formulation for topical and/or transdermal administrationof the imiquimod, which formulation comprises:

a) 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine, i.e., imiquimod, in anamount of about 2 percent to about 4 percent by weight based on thetotal weight of the formulation; and

b) a pharmaceutically acceptable vehicle for imiquimod, which vehiclecomprises a fatty acid, such as isostearic acid, linoleic acid, oleicacid, super purified oleic acid (an oleic acid having low polarimpurities such as peroxides) and a combination thereof, in a totalamount of about 3 percent to about 45 percent by weight based on thetotal weight of the formulation. The formulation is furthercharacterized in that when tested in the hairless mouse skin modeldescribed in U.S. Pat. No. 5,238,944, the formulation provides apenetration of the agent of at least about 10% (and preferably at leastabout 15%) of the total amount of the agent contained in the formulationin 24 hours.

The salient elements of a pharmaceutical formulation according to theinvention are (a) imiquimod and (b) a fatty acid, e.g., isostearic,linoleic, super purified oleic or oleic acid and mixtures thereof. Apharmaceutical formulation of the invention can be in any form known tothe art, such as a cream, an ointment, a foam, a gel, a lotion or apressure-sensitive adhesive composition, each form containing thenecessary elements in particular amounts and further containing variousadditional elements.

A cream of the invention preferably contains about 2 percent to about 4percent by weight of imiquimod based on the total weight of the cream;about 5 percent to about 25 percent by weight of fatty acid, based onthe total weight of the cream; and optional ingredients such asemollients, emulsifiers, thickeners, and/or preservatives.

An ointment of the invention contains an ointment base in addition toimiquimod and fatty acid. An ointment of the invention preferablycontains about 2 percent to about 4 percent by weight imiquimod; about 3percent to about 45 percent, more preferably about 3 percent to about 25percent by weight fatty acid; and about 40 percent to about 95 percentby weight ointment base, all weights being based on the total weight ofthe ointment. Optionally, an ointment of the invention can also containemulsifiers, emollients and thickeners.

A pressure-sensitive adhesive composition of the invention containsimiquimod, fatty acid, and an adhesive. The adhesives utilized in apressure sensitive adhesive composition of the invention are preferablysubstantially chemically inert to imiquimod. A pressure sensitiveadhesive composition of the invention preferably contains about 2percent to about 4 percent by weight imiquimod; about 10 percent toabout 40 percent by weight, more preferably of about 15 percent to about30 percent by weight, and most preferably about 20 percent to about 30percent by weight of fatty acid; all weights being based on the totalweight of the pressure sensitive adhesive composition.

Optionally, pressure sensitive adhesive compositions of the inventioncan also contain one or more skin penetration enhancers. The totalamount of skin penetration enhancer(s) present in a pressure sensitiveadhesive composition of the invention is preferably about 3 percent toabout 25 percent by weight, and more preferably about 3 percent to about10 percent by weight based on the total weight of the pressure sensitiveadhesive composition.

A pressure sensitive adhesive coated sheet material of the invention canbe made from a pressure-sensitive adhesive composition of the inventionin the form of an article such as a tape, a patch, a sheet, or adressing.

A formulation of the present invention may be used to topically and/ortransdermally administer imiquimod for effectively treating viralinfections, for example, Type I or Type II Herpes simplex infections,actinic keratosis and superficial basal cell carcinoma for a shorterduration of time and with the same or increased number of applicationsper week, as compared to current imiquimod topical therapy.

For example, a formulation of the present invention containing betweengreater than about 1% and about 5% imiquimod may be applied from threeto seven times per week (once per day) for 8 to 12 weeks to treat viralinfections, for example, Type I or Type II Herpes simplex infections,actinic keratosis and superficial basal cell carcinoma or to induceinterferon biosynthesis. It should be understood that while formulationsof the present invention containing between greater than about 1% andabout 5% imiquimod are preferred, formulations containing about 2.0%,2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5% aremore preferred and that formulations containing about 2.5%, 2.75%, 3.0%,3.25%, 3.5%, 3.75% and 4.0% are most preferred.

As to duration, the present invention contemplates applying an effectiveamount of imiquimod for a shorter period of time than currently approvedby the FDA. More specifically, the present invention contemplatesapplying an effective amount of imiquimod from three to seven times ormore per week to an area in need of imiquimod treatment for about 8 toabout 12 weeks, and more preferably between about 4, about 5, about 6and about 7 times a week for about 8, about 9 or about 10 weeks. Morepreferably, examples of shorter periods of treatment with low doseimiquimod for treating actinic keratosis and warts, e.g., externalgenital and perianal, as contemplated by the present invention comprise:

(a) applying an effective imiquimod dose of the lose dose imiquimodformulations, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, to the area affected withactinic keratosis, as follows: applying an effective amount once per dayfor fourteen (14) consecutive days, followed by no application forfourteen (14) days, followed by again applying an effective amount onceper day for fourteen (14) days for a total of twenty-eight (28) doses totreat actinic keratosis;

(b) applying an effective imiquimod dose of the lose dose imiquimodformulations, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, to the area affected withactinic keratosis, as follows: applying an effective amount once per dayfor twenty one (21) days, followed by no application for twenty one (21)days, followed by again applying an effective amount once per day fortwenty one (21) consecutive days for a total of forty-two (42) doses totreat actinic keratosis;

(c) applying an effective imiquimod dose of the lose dose imiquimodformulations to the warts, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%,3.25%, 3.5%, 3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, once per day,each day, for up to 56 consecutive days or 8 consecutive weeks or untilclearance is observed, which ever occurs earlier to treat the warts; or

(d) applying an effective imiquimod dose of a lose dose imiquimodformulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, to a dermatological area,once per day, each day, for:

(i) up to about 56 consecutive days or about 8 consecutive weeks toinduce effective interferon biosynthesis;

(ii) fourteen (14) days, followed by no application for fourteen (14)days, followed by again applying an effective amount imiquimod dose onceper day for fourteen (14) consecutive days for a total of twenty-eight(28) doses to induce effective interferon biosynthesis; or

(iii) twenty one (21) days, followed by no application for twenty one(21) days, followed by again applying an effective imiquimod dose onceper day for twenty one (21) consecutive days for a total of forty-two(42) doses to induce effective interferon biosynthesis.

While the present invention has identified what it believes to bepreferred concentrations of imiquimod, numbers of applications per weekand durations of therapy, it should be understood by those versed inthis art that any effective concentration of imiquimod in a formulationand any numbers of application per week that can accomplish a reductionin therapy duration to effectively treat Type I or Type II Herpessimplex infections, actinic keratosis and superficial basal cellcarcinoma or induce effective interferon biosynthesis is contemplated bythe present invention.

DETAILED DESCRIPTION OF THE INVENTION

As used in the specification and claims, the phrase “substantiallynon-irritating” designates formulations that do not cause unacceptableskin irritation in conventional repeat skin irritation tests in albinorabbits such as that described in Draize et al., “Appraisal of theSafety of Chemicals in Food, Drugs and Cosmetics”, prepared by theDivision of Pharmacology of the Food and Drug Administration, publishedoriginally in 1959 by the Association of Food and Drug Officials of theUnited States, Topeka, Kans. (2nd printing 1965), incorporated herein byreference.

The present invention provides pharmaceutical formulations such ascreams, ointments, foams, gels, lotions and adhesive coatings thatcontain imiquimod and a fatty acid such as isostearic, linoleic, superpurified oleic acid or oleic acid and mixtures thereof. The formulationsof the invention provide desirable skin penetrability of the imiquimod.

The compound imiquimod is a known antiviral agent that is also known toinduce interferon biosynthesis. It can be prepared using the methoddisclosed in U.S. Pat. No. 4,689,338, the disclosure of which isincorporated herein by reference. The compound can be used to treatviral infections such as Type I or Type II Herpes simplex infections andgenital warts. Furthermore, the fact that the compound is an interferoninducer suggests that it, and therefore formulations containing it,might be useful in the treatment of numerous other diseases, such asrheumatoid arthritis, warts, eczema, hepatitis B, psoriasis, multiplesclerosis, essential thrombocythaemia, and cancer, such as basal cellcarcinoma and other neoplastic diseases. The amount of imiquimod presentin a formulation of the invention will be an amount effective to treatthe targeted disease state to prevent the recurrence of such a diseaseor to promote immunity against such a disease. The amount is preferablyabout 0.5 percent to about 9 percent by weight based on the total weightof a formulation, more preferably between greater than about 1% andabout 5% imiquimod, and more preferably between about 2.0%, 2.25%, 2.5%,2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%, 4.25% and 4.5%, and mostpreferred between about 2.75%, 3.0%, 3.25%, 3.5%, 3.75% and 4.0%.Likewise, the shortened period or duration, as contemplated by thepresent invention, will be for reduced periods of time effective totreat the targeted disease as discussed herein above. By way of example,shorter periods of treatment with low dose imiquimod for treatingactinic keratosis and warts, e.g., external genital and perianal, orinducing interferon biosynthesis to achieve an effective antiviraleffect, include:

(a) applying an effective imiquimod dose of the lose dose imiquimodformulations, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, to the area affected withactinic keratosis, as follows: applying an effective amount once per dayfor fourteen (14) consecutive days, followed by no application forfourteen (14) days, followed by again applying an effective amount onceper day for fourteen (14) days for a total of twenty-eight (28) doses totreat actinic keratosis;

(b) applying an effective imiquimod dose of the lose dose imiquimodformulations, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%,4.0%, 4.25% or 4.5% imiquimod % w/w, to the area affected withactinic keratosis, as follows: applying an effective amount once per dayfor twenty one (21) days, followed by no application for twenty one (21)days, followed by again applying an effective amount once per day fortwenty one (21) consecutive days for a total of forty-two (42) doses totreat actinic keratosis;

(c) applying an effective imiquimod dose of the lose dose imiquimodformulations to the warts, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%,3.25%, 3.5%, 3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, once per day,each day, for up to 56 consecutive days or 8 consecutive weeks or untilclearance is observed, which ever occurs earlier to treat the warts; or

(d) applying an effective imiquimod dose of a lose dose imiquimodformulation, such as about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%, 4.25% or 4.5% imiquimod % w/w, to a dermatological area,once per day, each day, for:

(i) up to about 56 consecutive days or about 8 consecutive weeks toinduce effective interferon biosynthesis and an antiviral effect;

(ii) fourteen (14) days, followed by no application for fourteen (14)days, followed by again applying an effective amount imiquimod to amammal dose once per day for fourteen (14) consecutive days for a totalof twenty-eight (28) doses to induce effective interferon biosynthesisand an antiviral effect; or

(iii) twenty one (21) days, followed by no application for twenty one(21) days, followed by again applying an effective imiquimod dose onceper day for twenty one (21) consecutive days for a total of forty-two(42) doses to induce effective interferon biosynthesis and an antiviraleffect.

A fatty acid such as isostearic acid, linoleic acid, refined or superpurified oleic acid, unrefined oleic acid blended with effective amountsof antioxidants or mixtures thereof are incorporated into formulationsof the present invention. The total amount of fatty acid present in aformulation is preferably between about 3 percent and about 45 percentby weight based on the total weight of a formulation. It should beunderstood that when oleic acid is selected as a fatty acid, thatstability may present issue. Thus, stabilizers, such as anti-oxidantsand the like, may be required to preserve pharmaceutical elegance andstability over the life of the oleic acid formulation.

A pharmaceutical formulation of the invention can be in a form such as acream, an ointment, a foam, a gel, a lotion, a pressure-sensitiveadhesive composition, or other forms known to those skilled in the art,each particular form containing imiquimod and fatty acid in particularamounts, and optionally containing various additional elements. Thepreferred amounts of drug and fatty acid, and the amounts and types ofoptional elements used in formulations of the invention are discussedbelow with particular reference to creams, ointments and adhesivecompositions.

A cream according to the invention contains1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and fatty acid.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine present in acream is preferably about 0.5 percent to about 9 percent by weight, andmore preferably about 1 percent to about 5 percent by weight, based onthe total weight of the cream.

The total amount of fatty acid present in a cream of the invention ispreferably about 3 percent to about 45 percent by weight, and morepreferably about 5 percent to about 25 percent by weight, based on thetotal weight of the cream.

Optionally, a cream of the present invention can contain emollients,emulsifiers, thickeners, and/or preservatives.

Emollients such as long chain alcohols, e.g., cetyl alcohol, stearylalcohol and cetearyl alcohol; hydrocarbons such as petrolatum and lightmineral oil; or acetylated lanolin can be included in a cream of theinvention. A cream can contain one or more of these emollients. Thetotal amount of emollient in a cream of the invention is preferablyabout 5 percent to about 30 percent, and more preferably about 5 percentto about 10 percent by weight based on the total weight of the cream.

Emulsifiers such as nonionic surface active agents, e.g., polysorbate 60(available from ICI Americas), sorbitan monostearate, polyglyceryl-4oleate, and polyoxyethylene(4)lauryl ether or trivalent cationic a creamof the invention. A cream can contain one or more emulsifiers. Generallythe total amount of emulsifier is preferably about 2 percent to about 14percent, and more preferably about 2 percent to about 6 percent byweight based on the total weight of the cream.

Pharmaceutically acceptable thickeners, such as Veegum™K (available fromR. T. Vanderbilt Company, Inc.), and long chain alcohols (i.e. cetylalcohol, stearyl alcohol or cetearyl alcohol) can be used. A cream cancontain one or more thickeners. The total amount of thickener present ispreferably about 3 percent to about 12 percent by weight based on thetotal weight of the cream.

Preservatives such as methylparaben, propylparaben and benzyl alcoholcan be present in a cream of the invention. The appropriate amount ofsuch preservative(s) is known to those skilled in the art.

Optionally, an additional solubilizing agent such as benzyl alcohol,lactic acid, acetic acid, stearic acid or hydrochloric acid can beincluded in a cream of the invention.

If an additional solubilizing agent is used, the amount present ispreferably about 1 percent to about 12 percent by weight based on thetotal weight of the cream.

Optionally, a cream of the invention can contain a humectant such asglycerin, skin penetration enhancers such as butyl stearate, andadditional solubilizing agents.

It is known to those skilled in the art that a single ingredient canperform more than one function in a cream, i.e., cetyl alcohol can serveboth as an emollient and as a thickener.

Generally, a cream consists of an oil phase and a water phase mixedtogether to form an emulsion. Preferably, the amount of water present ina cream of the invention is about 45 percent to about 85 percent byweight based on the total weight of the cream.

The oil phase of a cream of the invention can be prepared by firstcombining the 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the fattyacid (if the cream contains benzyl alcohol it can also be added at thispoint) and heating with occasional stirring to a temperature of about50° C. to 85° C. When the 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amineappears to be completely dissolved, the remaining oil phase ingredientsare added and heating is continued until dissolution appears to becomplete.

The water phase can be prepared by combining all other ingredients andheating with stirring until dissolution appears to be complete.

The creams of the invention are generally prepared by adding the waterphase to the oil phase with both phases at a temperature of about 65° C.to 75° C. The resulting emulsion is mixed with a suitable mixerapparatus to give the desired cream.

An ointment of the invention contains an ointment base in addition to1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and fatty acid.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine present inan ointment of the invention is preferably about 0.5 percent to about 9percent, and more preferably about 0.5 percent to about 5 percent byweight based on the total weight of the ointment.

The total amount of fatty acid present in an ointment of the inventionis preferably about 3 percent to about 45 percent, and more preferablyabout 3 percent to about 25 percent based on the total weight of theointment.

A pharmaceutically acceptable ointment base such as petrolatum orpolyethylene glycol 400 (available from Union Carbide) in combinationwith polyethylene glycol 3350 (available from Union Carbide) can beused. The amount of ointment base present in an ointment of theinvention is preferably about 60 percent to about 95 percent by weightbased on the total weight of ointment.

Optionally, an ointment of the invention can also contain emollients,emulsifiers and thickeners. The emollients, emulsifiers, and thickenersand the preferred amounts thereof described above in connection withcreams are also generally suitable for use in an ointment of theinvention.

An ointment according to the invention can be prepared by combining1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine with fatty acid and heatingwith occasional stirring to a temperature of about 65° C. When the1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine appears to be completelydissolved, the remaining ingredients are added and heated to about 65.°C. The resulting mixture is mixed with a suitable mixer while beingallowed to cool to room temperature.

A pressure-sensitive adhesive composition of the invention contains1-isobutyl1H-imidazo[4,5-c]-quinolin-4-amine, fatty acid, and a pressuresensitive adhesive polymer.

The amount of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine present in apressure sensitive adhesive composition of the invention is preferablyabout 0.5 percent to about 9 percent by weight, and more preferablyabout 3 percent to about 7 percent by weight based on the total weightof the adhesive composition. The amount of fatty acid present ispreferably about 10 percent to about 40 percent by weight, morepreferably about 15 percent to about 30 percent by weight, and mostpreferably about 20 percent to about 30 percent by weight, based on thetotal weight of the adhesive composition.

Preferably, the adhesive polymer utilized in a pressure sensitiveadhesive composition of the invention is substantially chemically inertto 1-isobutyl-1Himidazo[4,5-c]quinolin-4-amine. The adhesive polymer ispreferably present in an amount of about 55 percent to about 85 percentby weight based on the total weight of the composition. Suitableadhesive polymers include acrylic adhesives that contain, as a majorconstituent (i.e., at least about 80 percent by weight of all monomersin the polymer), a hydrophobic monomeric acrylic or methacrylic acidester of an alkyl alcohol, the alkyl alcohol containing 4 to 10 carbonatoms. Examples of suitable monomers are those discussed below inconnection with the “A Monomer”. These adhesive polymers can furthercontain minor amounts of other monomers such as the “B Monomers” listedbelow.

Preferred adhesives include acrylic pressure-sensitive adhesivecopolymers containing A and B Monomers as follows: Monomer A is ahydrophobic monomeric acrylic or methacrylic add ester of an alkylalcohol, the alkyl alcohol containing 4 to 10 carbon atoms, preferably 6to 10 carbon atoms, more preferably 6 to 8 carbon atoms, and mostpreferably 8 carbon atoms. Examples of suitable A Monomers are n-butyl,n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl, isohexyl, 2-ethyloctyl,isooctyl and 2-ethylhexyl acrylates. The most preferred A Monomer isisooctyl acrylate.

Monomer B is a reinforcing monomer selected from the group consisting ofacrylic acid; methacrylic acid; alkyl acrylates and methacrylatescontaining 1 to 3 carbon atoms in the alkyl group; acrylamide;methacrylamide; lower alkyl-substituted acrylamides (i.e., the alkylgroup containing 1 to 4 carbon atoms) such as tertiary-butyl acrylamide;diacetone acrylamide; n-vinyl-2-pyrrolidone; vinyl ethers such as vinyltertiary-butyl ether; substituted ethylenes such as derivatives ofmaleic anhydride, dimethyl itaconate and monoethyl formate and vinylperfluoro-n-butyrate. The preferred B Monomers are acrylic acid,methacrylic acid, the above-described alkyl acrylates and methacrylates,acrylamide, methacrylamide, and the above-described lower alkylsubstituted acrylamides. The most preferred B Monomer is acrylamide.

In one embodiment of a pressure-sensitive adhesive composition of theinvention, the pressure-sensitive adhesive copolymer containing A and BMonomers as set forth above preferably contains the A Monomer in anamount by weight of about 80 percent to about 98 percent of the totalweight of all monomers in the copolymer. The A Monomer is morepreferably present in an amount by weight of about 88 percent to about98 percent, and is most preferably present in an amount by weight ofabout 91 percent to about 98 percent. The B Monomer in such a copolymeris preferably present in the pressure-sensitive adhesive copolymer in anamount by weight of about 2 percent to about 20 percent, more preferablyabout 2 percent to about 12 percent, and most preferably 2 to 9 percentof the total weight of the monomers in the copolymer.

In another embodiment of a pressure-sensitive adhesive composition ofthe invention, the adhesive copolymer comprises about 60 to about 80percent by weight (and preferably about 70 to about 80 percent byweight) of the above-mentioned hydrophobic monomeric acrylic ormethacrylic acid ester of an alkyl alcohol (i.e., Monomer A describedabove) based on the total weight of all monomers in the copolymer; about4 to about 9 percent by weight based on the total weight of all monomersin the copolymer of a reinforcing monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl-substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone; and about 15 to about 35percent by weight (and preferably about 15 to about 25 percent byweight) of vinyl acetate based on the total weight of all monomers inthe copolymer. In this embodiment the preferred acrylic or methacrylicacid ester is isooctyl acrylate and the preferred reinforcing monomer isacrylamide.

The above described adhesive copolymers are known, and methods ofpreparation therefor are well known to those skilled in the art, havingbeen described for example, in U.S. Pat. No. 24,906 (Ulrich), thedisclosure of which is incorporated herein by reference. Thepolymerization reaction can be carried out using a free radicalinitiator such as an organic peroxide (e.g., benzoylperoxide) or anorganic azo compound (e.g., 2,2′-azobis(2,4-dimethylpentanenitrile),available under the trade designation “Vazo 52” from DuPont).

Since pressure-sensitive adhesives such as those described above areinherently rubbery and tacky and are suitably heat and light stable,there is no need to add tackifiers or stabilizers. However, such can beadded if desired.

Optionally, a pressure sensitive adhesive composition of the inventioncan also contain one or more skin penetration enhancers such as glycerylmonolaurate, ethyl oleate, isopropyl myristate, diisopropyl adipate andN,N-dimethyldodecylamine-N-oxide, either as a single ingredient or as acombination of two or more ingredients. The skin penetration enhancer(s)preferably form a substantially homogeneous mixture with the pressuresensitive adhesive polymer or copolymer. The total amount of skinpenetration enhancer(s) present in a pressure sensitive adhesivecomposition of the invention is preferably about 3 percent to about 25percent by weight, more preferably about 3 percent to about 10 percentby weight based on the total weight of the adhesive composition.

When the skin penetration enhancer is a single ingredient, it ispreferably a skin penetration enhancer such as isopropyl myristate,diisopropyl adipate, ethyl oleate, or glyceryl monolaurate.

When a combination skin penetration enhancer is used, it is preferably acombination such as: ethyl oleate with glyceryl monolaurate; ethyloleate with N,N-dimethyldodecylamine-N-oxide; glyceryl monolaurate withN,N-dimethyldodecylamineN-oxide; and ethyl oleate with both glycerylmonolaurate and N,Ndimethyldodecylamine-N-oxide.

A pressure-sensitive adhesive composition of the invention can beprepared by combining dry adhesive,1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, fatty acid, and skinpenetration enhancer(s) with an organic solvent. The preferred organicsolvents are methanol and ethyl acetate. The total solids content of theadhesive coating is preferably in the range of about 15 percent to about40 percent, and more preferably in the range of about 20 to about 35percent based on the total weight of the adhesive coating. The resultingmixture is shaken or mixed for a period of about 20 to 72 hours. Whenthis method is used it is preferred that the1-isobutyl-1H-imidazo[4,5-4-quinolin-4-amine be in micronized form(i.e., particle size of 1-2 microns in diameter). Optionally, themixture can be heated during shaking.

In a preferred method, the 1-isobutyl-1H-imidazo-4,5-c]quinolin-4-amineis combined with the fatty acid and shaken at 40° C. until there appearsto be complete dissolution. The remaining ingredients are added and themixture is shaken for a period of about 20 to 72 hours.

The pressure-sensitive adhesive compositions described above arepreferably coated onto one surface of a suitable backing of sheetmaterial, such as a film, to form a pressure-sensitive adhesive coatedsheet material. A pressure-sensitive adhesive coated sheet material ofthe invention can be prepared by knife coating a suitable release linerto a predetermined uniform thickness with a wet adhesive formulation.This adhesive coated release liner is then dried and laminated onto abacking using conventional methods. Suitable release liners includeconventional release liners comprising a known sheet material, such as apolyester web, a polyethylene web, or a polystyrene web, orpolyethylene-coated paper, coated with a suitable silicone-type coatingsuch as that available under the trade designation Daubed 164Z, fromDaubed Co. The backing can be occlusive, non-occlusive or a breathablefilm as desired. The backing can be any of the conventional materialsfor pressure-sensitive adhesive tapes, such as polyethylene,particularly low density polyethylene, linear low density polyethylene,high density polyethylene, randomly-oriented nylon fibers,polypropylene, ethylene-vinylacetate copolymer, polyurethane, rayon andthe like. Backings that are layered, such aspolyethylene-aluminum-polyethylene composites are also suitable. Thebacking should be substantially non-reactive with the ingredients of theadhesive coating. The presently preferred backing is low densitypolyethylene.

The pressure-sensitive adhesive coated sheet material of the inventioncan be made in the form of an article such as a tape, a patch, a sheet,a dressing or any other form known to those skilled in the art.

Preferably, an article in the form of a patch is made from an adhesivecoated sheet material of the invention and applied to the skin of amammal. The patch is replaced as necessary with a fresh patch tomaintain the particular desired therapeutic effect of the1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.

Inherent Viscosity Measurement

The inherent viscosity values reported in the Examples below wereobtained by the conventional method used by those skilled in the art.The measurement of the viscosity of dilute solutions of the adhesive,when compared to controls run under the same conditions, clearlydemonstrates the relative molecular weights. It is the comparativevalues that are significant; absolute figures are not required. In theexamples, the inherent viscosity values were obtained using aCannon-Fenske #50 viscometer to measure the flow time of 10 ml of apolymer solution (0.2 g polymer/deciliter tetrahydrofuran, in a waterbath controlled at 25° C.). The examples and the controls were run underidentical conditions. The test procedure followed and the apparatus usedare explained in detail in the Textbook of Polymer Science, F. W.Billmeyer, Wiley-Interscience, 2nd Edition, 1971 under: Polymer chainsand their characterization, D. Solution Viscosity and Molecular Size, pp84-85, the disclosure and textbook of which is incorporated byreference.

The following examples are provided to illustrate the invention, but arenot intended to be limiting thereof. Parts and percentages are by weightunless otherwise specified. Examples of creams, ointments and pressuresensitive adhesive compositions contemplated by the present inventionare described in U.S. Pat. No. 4,689,338 and U.S. Pat. No. 5,238,944,which are incorporated herein by reference in their entireties. Percentmodifications for, e.g., imiquimod and vehicle, to generate imiquimodformulations as described herein are likewise contemplated by thepresent invention. In addition, the formulations described and disclosedin U.S. patent application Ser. No. 11/276,324, are also contemplated bythe present invention. Thus, U.S. patent application Ser. No.11/276,324, is incorporated herein by reference in its entirety.

Preparative Methods 1 Laboratory Scale Preparation ofIsooctylacrylate/Acrylamide Copolymer

To a 114 gram narrow-mouth glass bottle were added: 18.6 g isooctylacrylate, 1.4 g acrylamide, 0.04 g benzoyl peroxide, 27.0 g ethylacetate and 3.0 g methanol. The solution was purged for thirty fiveseconds with nitrogen at a flow rate of one liter per minute. The bottlewas sealed and placed in a rotating water bath at 55° C. for twenty-fourhours to effect essentially complete polymerization. The polymer wasdiluted with ethyl acetate/methanol (90/10) to 23.2 percent solids andhad a measured inherent viscosity of 1.26 dl/g in ethyl acetate.

Preparative Method 2 Pilot Plant Scale Preparation ofIsooctylacrylate/Acrylamide Copolymer

155 kg isooctylacrylate, 11.6 kg acrylamide, 209.1 kg ethyl acetate and23.2 kg methanol were charged to a clean, dry reactor. Medium agitationwas applied. The batch was deoxygenated with nitrogen while heating toan induction temperature of 55° C. 114 g Lucidol™70 initiator (availablefrom Pennwalt Corp.) mixed with 2.3 kg ethyl acetate was charged to thereactor. The temperature was maintained at 55° C. throughout thereaction. After 5.5 hours reaction time, 114 g Lucidol™70 mixed with 2.3kg ethyl acetate were charged to the reactor. After 9.0 hours reactiontime, an additional 114 g Lucidol™70 initiator mixed with 2.3 kg ethylacetate were charged to the reactor. The reaction was continued untilthe percent conversion was greater than 98 percent as measured by gaschromatographic evaluation of residual monomer concentration. Theresulting polymer solution was diluted to 25-28 percent solids withethyl acetate/methanol (90/10) and had a measured Brookfield viscosityof 17,000-21,000 centipoises using spindle #4 at 12 rpm. The polymer hada measured inherent viscosity of 1.3-1.4 dllg in ethyl acetate.

The above procedure was found to provide a pressure-sensitive adhesivethat is equivalent in the practice of the present invention to apressure-sensitive adhesive prepared according to PREPARATIVE METHOD 1.

A 25-30 percent solids solution of the isooctyl acrylate:acrylamide(93:7) adhesive copolymer in ethyl acetate/methanol (90:10) was coatedonto a two-sided release liner using a knife-coater and coating at 0.5mm in thickness. The adhesive-coated laminate was dried first at 82° C.for 3 minutes and then at 116° C. for 3 minutes. The dried adhesivecoating was then stripped off the release liner and placed in a glassbottle. The foregoing procedure results in a reduction of the amount ofany residual monomer in the adhesive copolymer.

Preparative Method 3 Preparation of Isooctyl Acrylate:Acrylamide:VinylAcetate (75:5:20) Copolymer

The procedure of PREPARATIVE METHOD 1 above acrylate, 8.0 g acrylamide,32.0 g vinyl acetate, 0.32 g benzoyl peroxide, 216.0 g ethyl acetate and24.0 g methyl alcohol. The resulting polymer was diluted with the ethylacetate/methyl alcohol mixture to 21.52% solids. The adhesive polymerhad a measured inherent viscosity of 1.40 dl/g in ethyl acetate at aconcentration of 0.15 g/dl. Its Brookfield viscosity was 2,300centipoise.

Preparative Method 4 Preparation of Isooctyl Acrylate Acrylamide:VinylAcetate (75:5:20) Copolymer

A master batch was prepared by combining 621.0 g of isooctyl acrylate,41.4 g of acrylamide, 165.6 g of vinyl acetate, 1.656 g of2,2′-azobis(2,4-dimethylpentanenitrile) (available from the DuPontCompany as Vazo™52), 884.52 g of ethyl acetate and 87.48 g of methanol.A 400 g portion of the resulting solution was placed in an amber quartbottle. The bottle was purged for two minutes with nitrogen at a flowrate of one liter per minute. The bottle was sealed and placed in arotating water bath at 45° C. for twenty-four hours to effectessentially complete polymerization. The copolymer was diluted with 250g of ethyl acetate/methanol (90/10) to 26.05% solids and had a measuredinherent viscosity of 1.27 dl/g in ethyl acetate at a concentration of0.15 g/dl. Its Brookfield viscosity was 5580 centipoise.

EXAMPLE 1

A cream according to the present invention is prepared from thefollowing ingredients:

Oil Phase % by Weight Amount 1-Isobuty1-1H-imidazo[4,5-c]- 1.0 40.0 gquinolin-4-amine Isostearic acid 10.0 400.0 g  Benzyl alcohol 2.0 80.0 gCetyl alcohol 2.2 88.0 g Stearyl alcohol 3.1 124.0 g  Polysorbate 602.55 102.0 g  Sorbitan monostearate 0.45 18.0 g Aqueous Phase Glycerin2.0 80.0 g Methylparaben 0.2  8.0 g Propylparaben 0.02  0.8 g Purifiedwater 76.48 3059.2 g The materials listed above were combined according to the followingprocedure:

The glycerin, methylparaben, propylparaben and water were weighed into a4 liter glass beaker then heated on a hot plate with stirring until theparabens isostearic acid and1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine were weighed into an 8liter stainless steel beaker and heated on a hot plate until the aminewas in solution (the temperature reached 69′C.). The benzyl alcohol,cetyl alcohol, stearyl alcohol, polysorbate 60 and sorbitan monostearatewere added to the isostearic acid solution and heated on a hot plateuntil all material was dissolved (the temperature reached 75° C.). Withboth phases at approximately the same temperature (65°-75° C.), thewater phase was added to the oil phase. The mixture was mixed with ahomogenizer for 13 minutes then put into a cool water bath and mixedwith a 3 inch propeller for 40 minutes (the temperature was 29° C.). Theresulting cream was placed in glass jars.

EXAMPLES 2-9

Using the general method of Example 1, the cream formulations shown inTables 1 and 2 are prepared.

TABLE 1 % by Weight Example Oil Phase 2 3 4 5 1-Isobuty1-1H-imidazo- 1.01.0 1.0 1.0 [4,5-e]quinolin-4-amine Isostearic acid 10.0 10.0 5.0 5.0Benzyl alcohol 2.0 — Cetyl alcohol 1.7 — Stearyl alcohol 2.3 — Cetearylalcohol 6.0 — 6.0 6.0 Polysorbate 60 2.55 2.55 2.55 2.55 Sorbitanmonostearate 0.45 0.45 0.45 0.45 Brij .TM. 30^(a) 10.0 Aqueous PhaseGlycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.2 0.2 0.2 Propylparaben0.02 0.02 0.02 0.02 Purified water 77.78 77.78 82.78 72.78 Brij .TM. 30(polyoxyethylene(4) lauryl ether) is available from ICI Americas, Inc.

TABLE 2 % by Weight Example 6 7 8 9 Oil Phase 1-Isobuty1-1H-imidazo- 1.01.0 1.0 1.0 r4,5-clquinolin-4-amine Isostearic acid 10.0 25.0 10.0 6.0Benzyl alcohol 2.0 2.0 Cetyl alcohol 2.2 1.7 Stearyl alcohol 3.1 2.3Cetearyl alcohol 6.0 — 6.0 Polysorbate 60 2.55 3.4 2.55 2.55 Sorbitanmonostearate 0.45 0.6 0.45 0.45 Brij .TM. 30 10.0 — Aqueous PhaseGlycerin 2.0 2.0 2.0 2.0 Methylparaben 0.2 0.2 0.2 0.2 Propylparaben0.02 0.02 0.02 0.02 Purified water 67.78 60.48 79.78 79.78

EXAMPLE 10

A cream according to the present invention is prepared from thefollowing ingredients:

% by Weight Amount Oil Phase 1-Isobuty1-1H-imidazo[4,5-4-quinolin-4- 1.03.00 g amine Isostearic acid 5.0 15.0 g White petrolatum 15.0 45.0 gLight mineral oil 12.8 38.4 g Aluminum stearate 8.0 24.0 g Cetyl alcohol4.0 12.0 g Witconol .TM. 14^(a) 3.0 9.00 g Acetylated lanolin 1.0  3.0 gPropylparaben 0.063 0.19 g Aqueous Phase Veegum .TM. K^(b) 1.0  3.0 gMethylparaben 0.12 0.36 g Purified water 49.017 147.05 g  ^(a)Witconol.TM. 14 (polyglyceryl4 oleate) is available from Witco Chemical Corp.Organics Division ^(b)Veegum .TM. K (colloidal magnesium aluminumsilicate) is available from R. T. Vanderbilt Company Inc.The materials listed above were combined according to the followingprocedure:

The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acidwere weighed into a glass jar and heated with occasional stirring untilthe amine was dissolved (the temperature reached 68° C.). To thissolution was added, the petrolatum, mineral oil, aluminum stearate,cetyl alcohol, Witconol™14, acetylated lanoline and propylparaben. Themixture was heated to 75° C. In a separate beaker, the methylparaben andwater were combined and heated until the paraben dissolved (thetemperature reached 61° C.). The Veegum™K was added to the aqueoussolution and heated at 75° C. for 30 minutes while mixing with ahomogenizer. With both phases at 75° C., the aqueous phase was slowlyadded to the oil phase while mixing with a homogenizer. Mixing wascontinued for 30 minutes while maintaining a temperature to about 80° C.The jar was then capped and the formulation was allowed to cool.

EXAMPLE 11

An ointment according to the present invention is prepared from thefollowing ingredients:

% by Weight Amount 1-Isobuty1-1H-imidazo[4,5-c]quinolin-4- 1.0 0.20 gamine Isostearic acid 5.0 1.00 g Mineral oil 12.8 2.56 g Whitepetrolatum 65.2 13.04 g  Cetyl alcohol 4.0 0.80 g Acetylated lanolin 1.00.20 g Witconol .TM. 143.0 0.60 g Aluminum stearate 8.0 1.60 gThe materials listed above are combined according to followingprocedure:

The 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and the isostearic acidwere placed in a glass jar and heated with stirring until the amine wasdissolved. The remaining ingredients were added and the resultingmixture was heated to 65° C. and then mixed while being allowed to coolto room temperature.

EXAMPLE 12

Using the general procedure of Example 11 an ointment containing thefollowing ingredients is prepared.

% by Weight Amount 1-Tsobuty1-1H-imidazo[4,5-c]-quinolin- 1.0 0.20 g4-amine Isostearic acid 6.0 1.20 g Polyethylene Glycol 400 55.8 11.16 g Polyethylene Glycol 3350 32.6 6.52 g Stearyl alcohol 4.6 0.92 g

EXAMPLES 13-15

Creams of the present invention are prepared using the ingredients shownin Table 3. The Example 1 except that benzyl alcohol was used with theisostearic acid to dissolve the 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.

TABLE 3 Example 13 14 15 % by Weight Oil Phase1-Isobuty1-1H-imidazo[4,5-4-quinolin-4- 5.0 5.0 4.85 amine Isostearicacid 25.0 25.0 24.3 Benzyl alcohol 2.0 2.0 1.94 Cetyl alcohol 2.2 2.21.16 Stearyl alcohol 3.1 3.1 1.75 Petrolatum 3.0 2.91 Polysorbate 60 3.43.4 4.13 Sorbitan monostearate 0.6 0.6 0.73 Stearic acid 9.71 AqueousPhase Glycerin 2.0 2.0 1.94 Methylparaben 0.2 0.2 0.19 Propylparaben0.02 0.02 0.02 Purified water 53.48 56.48 46.39

EXAMPLE 16

A cream according to the present invention is prepared from thefollowing ingredients:

% by Weight Amount Oil Phase 1-Isobuty1-1H-imidazo[4,5-c]-quinolin-4-4.0 0.80 g amine Isostearic acid 20.0 4.00 g Benzyl alcohol 2.0 0.40 gCetyl alcohol 2.2 0.49 g Stearyl alcohol 3.1 0.62 g Polysorbate 60 3.40.68 g Sorbitan monostearate 0.6 0.12 g Aqueous Phase1-Isobuty1-1H-imidazo [4,5-c]-quinolin-4- 1.0  0.2 g amine Glycerin 2.0 0.4 g 85% Lactic acid 1.0 0.22 g Methylparaben 0.2 0.04 g Propylparaben0.02 0.004 g  Purified water 60.48 12.0 gThe materials listed above are combined according to the followingprocedure:

The isostearic acid and 0.8 g of1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine were combined in a glassjar and heated with stirring until the amine had dissolved. Theremaining oil phase ingredients were added to this solution and themixture was heated to about 70° C. The aqueous phase ingredients wereweighed into a separate beaker and heated with stirring until the amineand the parabens had dissolved. With both phases at about 70° C., thewater phase was added to the oil phase and mixed with a propeller untilthe mixture cooled to room temperature.

EXAMPLE 17

A mixture of 5.9415 g of the 93:7 isooctyl acrylate:acrylamide adhesivecopolymer prepared in PREPARATIVE METHOD 2 above, 1.5126 g isostearicacid, 2.0075 g ethyl oleate, 0.3021 g glyceryl monolaurate, 0.29361-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (micronized) and 23.7 g of90:10 ethyl acetate:methanol was placed in a small glass jar. The jarwas placed on a horizontal shaker and shaken at room temperature forabout 13 hours. The formulation was coated at a thickness of 20 milsonto a 5 mil Daubed 164Z liner. The laminate was oven dried for 3minutes at 105° F., for 2 minutes at 185° F., and for 2 minutes at 210°F. The resulting adhesive coating contained 59.1 percent 93:7 isooctylacrylate:acylamide adhesive copolymer, 15.0 percent isostearic acid,20.0 percent ethyl oleate, 3.0 percent glyceryl monolaurate and 2.9percent 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine. The material wasthen laminated with 3 mil low density polyethylene backing and die cutinto 2.056 cm.sup.2 patches.

EXAMPLES 18-20 Pressure-Sensitive Adhesive Coated Sheet MaterialsPrepared Using Unmicronized 1-Isobutyl-1H-imidazo[4,5-c]quinolin-4-amine

Using the general method of Example 17 the formulations shown below areprepared. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-4-amine that had beenground with a mortar and pestle was used. The adhesive was the 93:7isooctyl acrylate:acrylamide copolymer prepared in PREPARATIVE METHOD 1above. The solvent was 90:10 ethyl acetate:methanol. All formulationswere mixed at room temperature.

Example 18 19 20 1-Isobuty1-1H-imidazo[4,5-0- 5.0 3.0 3.0quinolin-4-amine Ethyl oleate 5.1 5.0 8.0 Isostearic acid 10.0 10.0 6.0Oleic acid 20.0 20.0 13.0 Glyceryl monolaurate 1.5 1.5 1.5N,N-dimethyldodecylamine- 1.0 1.1 3.0 N-oxide Adhesive 57.4 59.3 65.4

EXAMPLE 21

A formulation with the same components in the same proportions asExample 18 is prepared using a different method. The1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine was combined with theoleic and isostearic acids and shaken at 40° C. until there was completedissolution of the 1-isobutyl-1H-imidazo-[4,5-c]quinolin-4-amine. Theremaining ingredients were added and shaken a 40° C. for 72 hours.Patches measuring 2.056 cm.sup.2 were prepared by the general method ofExample 17.

EXAMPLE 22

A mixture of 2.4734 g 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine3.3315 g isostearic acid and 6.6763 g oleic acid is prepared. To 1.8738g of the above mixture was added 2.8750 g of the 93:7 isooctylacrylate:acryamide adhesive copolymer prepared in PREPARATIVE METHOD 2above, 0.2548 g of ethyl oleate, 0.0510 gN,N-dimethyldodecylamine-N-oxide, 0.0820 g glyceryl monolaurate (fromLauricidin, Inc.) and 14.0457 g of 90:10 ethyl acetate/methanol. Theabove was shaken for 30 hours at room temperature on a horizontalshaker. Transdermal patches were then prepared generally according tothe procedures of Example 17.

EXAMPLE 23

Creams are prepared in accordance with the present invention using theingredients shown in this Example 23.

Excipients % w/w % w/w % w/w % w/w % w/w Isostearic Acid 10.00 12.5025.00 10.00 15.00 Cetyl alcohol 2.20 2.20 2.70 4.00 4.00 Stearyl alcohol3.10 3.10 3.80 2.00 2.00 White petroleum 5.00 5.00 3.00 3.40 2.80Polysorbate 60 3.40 3.40 3.40 3.80 3.00 Sorbitan Monostearate 0.60 0.600.60 1.00 1.00 Glycerin 5.00 5.00 2.00 1.00 3.00 Xanthan gum 0.50 0.500.50 0.30 0.70 Purified water 65.98 63.48 54.78 70.28 64.28 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.00 2.00 2.00 2.002.00 Total: 100.00 100.00 100.00 100.00 100.00

EXAMPLE 24

Creams are prepared in accordance with the present invention using theingredients shown in this Example 24.

Excipients % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.00 12.5025.00 15.00 10.00 Cetyl alcohol 2.20 2.20 2.20 2.00 2.00 Stearyl alcohol3.10 3.10 3.10 2.00 2.40 White petroleum 6.00 5.00 3.00 3.40 2.80Polysorbate 60 3.00 3.00 3.40 3.80 3.80 Sorbitan Monostearate 1.00 1.000.60 0.20 1.00 Glycerin 5.00 5.00 2.00 3.00 3.00 Xanthan gum 1.00 0.501.00 0.30 0.30 Purified water 60.23 63.23 55.23 66.83 70.23 Benzylalcohol 1.00 2.00 2.00 1.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.25 2.25 2.25 2.252.25 Total: 100.00 100.00 100.00 100.00 100.00

EXAMPLE 25

Creams are prepared in accordance with the present invention using theingredients shown in this Example 25.

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.0015.00 10.00 20.00 15.00 20.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.20 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10 White 15.50 3.00 8.503.00 6.00 3.00 petroleum Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00Sorbitan 0.60 0.60 0.60 0.60 1.00 1.00 Monostearate Glycerin 2.00 2.005.00 2.00 5.00 3.00 Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75 Purifiedwater 52.98 65.48 61.98 60.48 59.23 59.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50Total: 100.00 100.00 100.00 100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.0015.00 15.00 25.00 12.5 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White 3.00 6.00 6.00 3.005.00 3.00 petroleum Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 65.48 59.48 59.48 55.48 62.98 54.28 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50Total 100.00 100.00 100.00 100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 25.0015.00 20.00 20.00 20.00 20.00 Cetyl alcohol 2.20 2.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10 White 3.00 3.40 5.003.00 5.00 3.00 petroleum Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 0.2 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 2.00 Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50 Purifiedwater 54.98 65.58 58.48 57.48 55.48 60.48 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50Total 100.00 100.00 100.00 100.00 100.00 100.00

EXAMPLE 26

Creams are prepared in accordance with the present invention using theingredients shown in this Example 26.

Excipients % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.00 18.0015.00 20.00 12.50 Cetyl alcohol 2.00 2.00 2.00 2.00 2.20 Stearyl alcohol2.00 2.00 2.40 2.40 3.10 White petroleum 3.40 2.80 3.40 2.80 5.00Polysorbate 60 3.00 3.80 3.00 3.00 3.40 Sorbitan Monostearate 1.00 1.000.20 0.20 0.60 Glycerin 3.00 2.00 1.00 3.00 6.00 Xanthan gum 0.30 0.700.70 0.30 0.50 Purified water 65.08 62.48 67.08 61.08 61.48 Benzylalcohol 2.00 2.00 2.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.00 3.00 3.00 3.003.00 Total: 100.00 100.00 100.00 100.00 100.00

EXAMPLE 27

Creams are prepared in accordance with the present invention using theingredients shown in this Example 27.

Excipients % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.00 20.0015.00 20.00 10.00 Cetyl alcohol 2.00 2.00 4.00 4.00 2.20 Stearyl alcohol2.00 2.40 2.40 2.40 3.10 White petroleum 3.40 2.80 2.50 3.40 5.00Polysorbate 60 3.00 3.00 3.00 3.80 3.40 Sorbitan Monostearate 1.00 0.201.00 1.00 0.60 Glycerin 3.00 3.00 1.00 3.00 5.00 Xanthan gum 0.30 0.300.30 0.70 0.50 Purified water 64.83 60.83 65.33 57.23 64.73 Benzylalcohol 2.00 2.00 2.00 1.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.25 3.25 3.25 3.253.25 Total: 100.00 100.00 100.00 100.00 100.00

EXAMPLE 28

Creams are prepared in accordance with the present invention using theingredients shown in this Example 28.

Excipients % w/w % w/w % w/w % w/w % w/w Isostearic Acid 15.00 10.0012.50 19.00 20.00 Cetyl alcohol 2.00 2.20 2.20 2.20 2.20 Stearyl alcohol2.40 3.10 3.10 3.10 3.10 White petroleum 3.40 5.00 5.00 3.00 3.00Polysorbate 60 3.00 3.40 4.00 3.40 3.40 Sorbitan Monostearate 0.20 0.600.60 0.60 0.60 Glycerin 1.00 4.00 5.00 2.00 6.00 Xanthan gum 0.70 0.500.50 0.50 0.50 Purified water 66.58 65.48 61.38 60.48 56.48 Benzylalcohol 2.00 2.00 2.00 2.00 1.00 Methylparaben 0.20 0.20 0.20 0.20 0.20Propylparaben 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.50 3.50 3.50 3.503.50 Total: 100.00 100.00 100.00 100.00 100.00

EXAMPLE 29

Creams are prepared in accordance with the present invention using theingredients shown in this Example 29.

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 20.0020.00 25.00 18.75 20.00 21.25 Cetyl alcohol 4.00 2.20 2.20 2.20 2.202.20 Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10 White 3.40 3.00 3.005.00 5.00 3.75 petroleum Polysorbate 60 3.80 3.40 3.40 3.00 3.40 3.40Sorbitan 1.00 0.60 0.60 1.00 0.60 0.60 Monostearate Glycerin 3.00 2.002.00 5.00 5.00 5.00 Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.50 Purifiedwater 55.73 59.23 54.23 55.48 54.23 54.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75Total: 100.00 100.00 100.00 100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 20.0020.00 20.00 25.00 18.75 25.00 Cetyl alcohol 2.20 2.20 2.20 2.20 2.202.70 Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80 White 3.00 6.00 6.003.00 5.00 3.00 petroleum Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40Sorbitan 0.60 0.60 1.00 0.50 1.00 0.60 Monostearate Glycerin 2.00 5.005.00 2.00 5.00 2.00 Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purifiedwater 59.23 53.23 53.23 54.23 55.48 53.03 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75Total 100.00 100.00 100.00 100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 25.0020.00 20.00 20.00 20.00 21.00 Cetyl alcohol 2.20 4.00 2.20 2.20 2.202.20 Stearyl alcohol 3.10 2.40 3.10 3.10 3.10 3.10 White 3.00 3.40 5.003.00 5.00 5.00 petroleum Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40Sorbitan 0.60 1.00 0.60 0.60 0.60 0.60 Monostearate Glycerin 2.00 3.002.00 5.00 5.00 5.00 Xanthan gum 1.00 0.70 0.50 0.50 0.50 0.50 Purifiedwater 53.73 55.73 57.23 56.23 54.23 53.23 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75Total 100.00 100.00 100.00 100.00 100.00 100.00

EXAMPLE 30

Creams are prepared in accordance with the present invention using theingredients shown in this Example 30.

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Isostearic Acid 20.0025.00 22.50 20.00 20.00 22.50 Cetyl alcohol 2.20 2.70 2.20 4.00 2.202.20 Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10 White 6.00 3.00 3.003.40 5.00 4.00 petroleum Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40Sorbitan 1.00 0.60 0.60 1.00 0.60 0.60 Monostearate Glycerin 5.00 2.002.00 3.00 2.00 2.00 Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50 Purifiedwater 52.98 52.78 55.98 55.48 56.98 55.48 Benzyl alcohol 2.00 2.00 2.002.00 2.00 2.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Propylparaben0.02 0.02 0.02 0.02 0.02 0.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00Total 100.00 100.00 100.00 100.00 100.00 100.00

EXAMPLE 31

Creams are prepared in accordance with the present invention using theingredients shown in this Example 31.

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 6.00 6.00 6.00 6.00 6.00 6.00 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 5.75 5.75 5.75 5.75 5.75 5.75 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 5.50 5.50 5.50 5.50 5.50 5.50 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 5.25 5.25 5.25 5.25 5.25 5.25 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 2.75 2.75 2.75 2.75 2.75 2.75 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 5.00 5.00 5.00 5.00 5.00 5.00 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 4.75 4.75 4.75 4.75 4.75 4.75 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 4.50 4.50 4.50 4.50 4.50 4.50 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 4.25 4.25 4.25 4.25 4.25 4.25 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 4.00 4.00 4.00 4.00 4.00 4.00 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 3.75 3.75 3.75 3.75 3.75 3.75 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25 Total 100.00 100.00 100.00100.00 100.00 100.00

Excipients % w/w % w/w % w/w % w/w % w/w % w/w Oleic acid 7.40 7.40 7.407.40 7.40 Stearic acid 3.00 3.00 3.00 Linoleic acid 25.0 Oleyl alcohol10.0 10.0 Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20 Stearyl alcohol3.10 3.10 3.10 3.10 3.10 3.10 Sorbitol 70% 30.0 Castor oil 15.0 Lacticacid 5.00 Urea 5.00 White 3.50 3.50 3.50 3.50 3.50 3.50 petroleumPolysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40 Sorbitan 0.60 0.60 0.600.60 0.60 0.60 Monostearate Glycerin 2.00 2.00 2.00 2.00 2.00 2.00Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50 Purified water 67.58 60.5857.58 52.98 52.98 43.58 Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Citric acid 0.13 monohydrateAmmonium 2.00 hydroxide solution Propylparaben 0.02 0.02 0.02 0.02 0.020.02 Imiquimod 4.50 4.50 4.50 4.50 4.50 4.50 Total 100.00 100.00 100.00100.00 100.00 100.00

It is believed that the creams of the present invention haveHydrophilic-lipophilic balance (HIB) values between about 12 and 15, andmore preferably between about 12.4 and about 13.4.

1. A method for treating genital or perianal warts in a subject, themethod comprising: applying an imiquimod pharmaceutical cream formulatedwith 3.75% by weight imiquimod to the warts, once per day, each day, forup to about 8 consecutive weeks or until clearance is observed,whichever occurs earlier, to treat the warts.
 2. The method of claim 1,wherein the imiquimod pharmaceutical cream further comprises apharmaceutically acceptable vehicle.
 3. The method of claim 2, whereinthe pharmaceutically acceptable vehicle comprises a member selected fromthe group consisting of a fatty acid, an emollient, an emulsifier, athickener, a preservative, a humectant, water, or a combination thereof.4. The method of claim 3, wherein the fatty acid is selected from thegroup consisting of isostearic acid, linoleic acid, oleic acid, superpurified oleic acid, and a combination thereof
 5. The method of claim 3,wherein the fatty acid is isostearic acid.
 6. The method of claim 3,wherein the fatty acid is present in an amount of between about 5% toabout 25% by weight.
 7. The method of claim 3, wherein the emollient isselected from the group consisting of cetyl alcohol, stearyl alcohol,petrolatum, and a combination thereof.
 8. The method of claim 3, whereinthe emollient is present in an amount of between about 5% to about 10%by weight.
 9. The method of claim 3, wherein the emulsifier is selectedfrom the group consisting of polysorbate 60, sorbitan monostearate, anda combination thereof
 10. The method of claim 3, wherein the emulsifieris present in an amount of between about 2% to about 6% by weight. 11.The method of claim 3, wherein the preservative is selected from thegroup consisting of methylparaben, propylparaben, benzyl alcohol, and acombination thereof
 12. The method of claim 3, wherein the humectant isglycerin.
 13. The method of claim 3, wherein the water is present in anamount of between about 45% to about 85% by weight.
 14. The method ofclaim 2, wherein the pharmaceutically acceptable vehicle consists ofisostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum,polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, water,benzyl alcohol, methylparaben, and propylparaben.
 15. The method ofclaim 1, wherein the imiquimod pharmaceutical cream is selected from thegroup of 3.75% imiquimod pharmaceutical creams listed in Example 29.